392 replies to this topic

[able]

It is really not new that NMN can increase NAD+ inside cells by converting to NR first. Yes, in this specific cell study, NMN seems to be slightly productive on equal molar basis. Remember NMN is 31% heavier than NR. If you normalize to equal weight basis, NR will be more effective.

 

 

Ok. So you admit that the theory Dr Brenner depends on for why NR is better than NMN is nonsense.  

 

That is progress.  Thanks.

Edited by able, 08 December 2019 - 01:05 AM.

[MikeDC]

Ok. So you admit that the theory Dr Brenner depends on for why NR is better than NMN is nonsense.

That is progress. Thanks.

That is not nonsense. One cell line study does not make a trend. Oral supplementation is much more complicated. Brenner May give us the answer when his comparison study is published. The truth will come out eventually. My opinion is current formulation of NR and NMN have very poor bioavailability. New formulations are needed to improve bioavailability.

[Ken Mark]

Nicotinic Acid (NA) has excellent bioavailability, the flush tells you that. NR, NMN and NAM itself increase NAD+ through salvage pathway, where as NA and Tryptophan increase NAD+ through PH or de novo pathways.

If the goal is to increase NAD+, NA and Tryptophan are better supplements than NAM or it's precursors NR/NMN as they overburden the salvage pathway.

And NAD+ created and used up by the body will eventually be salvaged so NA and Tryptophan will also do what you're trying to accomplish via NR/NMN/NAM (meaning, NA and Tryptophan work for you twice at least), so I don't really understand why would anyone choose anything otherthan NA or Tryptophan if the goal is to increase NAD+.

What am I missing?

[aribadabar]

What am I missing?

 

The obvious - that the salvage pathway is much less complicated/more efficient than the de novo one to generate same amount of NAD+?

[p75213]

NAD+ is salvaged to NAM so why isn't there more emphasis on supporting the nampt and Nmnat enzymes?

[Joe Garma]

I think many of the questions asked in this thread can be answered by watching Dr. Rhonda Patrick interview Dr. Sinclair.

 

He gets into the NAD salvage pathway and explains the basic reason we want to increase levels of NAD, which is to support sirtuins, our so-called "longevity genes."

 

You can find the video and my review of it here: https://www.garmaonh...ongevity-genes/

[able]

We get around 85% of our NAD+ through the salvage pathway, so it is more important than de novo.

 

NAMPT is the bottleneck in the salvage pathway.  Increasing NAMPT is one approach.

 

The allure of NMN and NR is that the feed into the salvage pathway AFTER the NAMPT bottleneck.

 

I dont see why it has to be one or the other.  I like taking Niacin and NMN both.

[p75213]

We get around 85% of our NAD+ through the salvage pathway, so it is more important than de novo.

 

NAMPT is the bottleneck in the salvage pathway.  Increasing NAMPT is one approach.

 

The allure of NMN and NR is that the feed into the salvage pathway AFTER the NAMPT bottleneck.

 

I dont see why it has to be one or the other.  I like taking Niacin and NMN both.

However  that NMN/NR/NAM is converted to NAD+, the NAD+ is salveged back to NAM and that's when the NAMPT bottleneck presents itself no matter the original precursor.

[MikeDC]

Now Sinclair is finally convinced

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[Linux]

Now Sinclair is finally convinced

 

...finally convinced of what? Sinclair´s tweet is specifically talking about kidney cells in a petri dish. There may be different uptake dynamics from tissue to tissue. 

 

It´s fruitless to come to some sort of definite conclusion right now in this evolving field of NAD-metabolism. 

 

We don´t even know exactly how NR is transported (ENT?) and much more is to be uncovered about the NMN transporter and NAD distribution and uptake in different cell types and under different conditions.

Edited by Linux, 10 December 2019 - 01:27 PM.

[MikeDC]

...finally convinced of what? There may be different uptake dynamics from tissue to tissue. Sinclair´s tweet is specifically talking about kidney cells in a petri dish.

It´s fruitless to come to some sort of definite conclusion right now in this evolving field of NAD-metabolism.

We don´t even know exactly how NR is transported (ENT?) and much more is to be uncovered about the NMN transporter and NAD distribution and uptake in different cell types and under different conditions.

This study used kidney cells. Other studies used other cell. Beside one research group who claims there is a NMN transporter, all other studies show NMN needs to convert to NR before entering cells.

[Linux]

Now Sinclair is finally convinced

 

What is Sinclair "finally" convinced of?

Edited by Linux, 10 December 2019 - 01:31 PM.

[able]

Now Sinclair is finally convinced

 

 

All Sinclair is doing is giving an honest interpretation of a study result.

 

He hasn't told anyone to put down the NMN and buy Tru Niagen.

 

As you admitted above, this study shows NMN is more effective than NR at restoring NAD+ levels inside the cells, even though it drops its phosphate to convert to NR to cross the membrane.

 

This study also shows NR is quickly hydrolyzed to NAM in plasma, so is never prevalent in the bloodstream.  The phospate makes NMN and NAD+ far more stable so they survive in the bloodstream.

 

NR is not stable in blood.  It is merely the form used to cross the membrane in some cells - it is not used by the body to transport in the bloodstream.  

 

NAD+ and NMN are used to transport, then quickly convert to NR to go that last step in some cells, as confirmed by this study.

Edited by able, 10 December 2019 - 02:21 PM.

[MikeDC]

Only double labeled isotopes study in vivo can reflect realty in mice anyway. The ling liu’s Study showed Oral NR generates more double labeled NAD+ than NMN.
Brenner’s quantitive study will be published early next year. That will tell us which precursor works better.

[able]

I think my explanation in another thread made the most sense why NMN generated more NAD+ in the kidney while NR generates more NAD+ in all other tissues. We know that Ling Liu’s Dissertation shows that NMN disappears from blood quickly even after IV supplementation. NMN is much less bioavailable than NR in the blood. The proposed reason for this is NMN is stuck in the kidney tissue when blood is filtered at kidney. This concentrated NMN generated more NAD+ in the kidney. This doesn’t mean NMN can get into cells without converting to NR first in kidney cells. Sinclair’s mention of NMN and NR behave differently in different cells is just pumping NMN without any solid evidence. So far there is no data that shows NMN can get into cells while all data shows NR can get into all cells tested. NAD+ can actually get into cells without converting to NR first. The discussion of NR and NMN supplementation starts at page 32.

 

  https://dataspace.pr...0181D_12390.pdf

 

Another issue with NMN is not all NMN are converted to NR, a lot of NMN are metablized and flushed out in the urine.

 

 

Desparate to change the subject?  You brought up the most recent study again, that Dr Sinclair tweeted about.

 

I pointed out some facts about that study, that you agreed to above.

 

 

Yes, in this specific cell study, NMN seems to be slightly productive on equal molar basis. 

 

I'm not aware of where Ling Lui shows NMN is not stable in the blood.  Got a quote from that study?

 

Here's a few from this most recent study you might have missed:

 

 

In the presence of cells, NMN was degraded faster, but even under these conditions, after 24 and 48 h still 80% and 60%, respectively, of the added mononucleotide were present in the medium

 NMN exhibited rather high stability in cell culture, but was partially metabolized to NR.

Surprisingly, NR was also rather efficiently hydrolyzed to Nam.

 

 

 

 

and another from the study that Dr Brenner purposely disregards:

 

On the other hand, there are several studies supporting the direct uptake of NMN or NAD⁺ into human cells [13,23,24].

 

[MikeDC]

This chart is from ling liu’s Paper. You can see NR produces higher double labeled NAD+ than NMN.
IV-NR produced significant double labeled NAD+ while NMN produced close to none.
This means that NMN can’t convert to NR in the muscle.

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Edited by MikeDC, 10 December 2019 - 05:43 PM.

[Linux]

This chart is from ling liu’s Paper. You can see NR produces higher double labeled NAD+ than NMN.
IV-NR produced significant double labeled NAD+ while NMN produced close to none.
This means that NMN can’t convert to NR in the muscle.

 

How is ANY data from IV NR relevant to the human oral supplementation of NR or NMN? Neither NR nor NMN is given by infusion to humans.

Edited by Linux, 10 December 2019 - 05:56 PM.

[MikeDC]

How is ANY data from IV NR relevant to the human oral supplementation of NR or NMN? Neither NR nor NMN is given by infusion to humans.

It is relevant because it is the best case for oral supplementation. When IV NMN can’t produce double labeled NaD+, oral NMN will definitely produce less.

[able]

It is relevant because it is the best case for oral supplementation. When IV NMN can’t produce double labeled NaD+, oral NMN will definitely produce less.

 

So you are conceding that the human kidney cells study shows no benefit for NR at crossing the cell membrane, and now changing to argue about another tissue type in a different study?

[MikeDC]

So you are conceding that the human kidney cells study shows no benefit for NR at crossing the cell membrane, and now changing to argue about another tissue type in a different study?

In vivo studies overwrite in vitro studies.

[MikeDC]

NMN is not stable at room temperature according to Sinclair.

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Edited by MikeDC, 21 December 2019 - 09:33 PM.

[p75213]

Why is NAD+ not discussed? It's either NMN or NR. NAD+ powder is available and piping rock sell capsules so somebody must be taking it. Does anybody have any experience using NAD+?

[Linux]

Oral NAD in rats gets broken down into NR, NMN and nicotinamide in the GI tract.

I see no reason taking it, you have NAD in unprocessed whole food already.

By taking NR/NMN you don't get the added nicotinamide (from start at least).

[able]

Oral NAD in rats gets broken down into NR, NMN and nicotinamide in the GI tract.

I see no reason taking it, you have NAD in unprocessed whole food already.

By taking NR/NMN you don't get the added nicotinamide (from start at least).

 

I have never understood this reasoning.

 

NAD+ gets broken down to NMN and NR in the gut.

 

 Subsequently, that then gets mostly broken down to NAM.

 

I cannot see how it would be more completely metabolized that if you just start with NR or NMN.

 

It seems possible MORE NAD+ survives digestion as NR,NMN, or NAD+, but not less.

[MikeDC]

A recent study shows NRCL is very stable in the fluid of stomach and intestine.

[able]

 

Many studies show NR is not stable in blood, for instance:

 

A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor

 

 

NR quickly disappears from the bloodstream, and is almost undetectable 1 h after intraperitoneal administration at 500 mg/kg. 

 

Elegant tracer experiments demonstrated that after oral intake, NR was utilized as such by the liver, while it predominantly reached the peripheral tissues as its degradation product, NAM.

 

 

 

Edited by able, 26 December 2019 - 04:39 PM.

[p75213]

Considering the price of Nr/nmn/NAD+ and the fact it is mostly broken down in the gut to nam. Why not just supplement with nam and some additional supplements to activate nampt. In any case, after NAD+ is used by the parps/cd38/sirtuins it is subsequently broken down to nam for another circuit around the salvage pathway.
What am I missing?

[Fredrik]

A recent study shows NRCL is very stable in the fluid of stomach and intestine.

 

The study you are misrepresenting concluded that NR breaks down to regular B3 and sugar in the intestines:

 

"...here we have reported that NR is a labile molecule with defined and absolute upper limits for processing and handling.

An active effort must be made to preclude breakdown of the NR molecule during the development of new NR products and upon its delivery for supplementation.

NR is predicted to not be stable in the GI tract, post stomach transit."

 

https://www.longecit...ch/#entry883355

Edited by Fredrik, 26 December 2019 - 08:53 PM.

[MikeDC]

The authors are just trying to make headlines to grab attention. The data does not warrant that conclusion. Always look at the data.

[Oakman]

What I want to know is, where and when is this NRH available to us? Usually, Amazon (and others - Chromadex are you listening?) has vendors just waiting to unload new molecules on us. Is it so difficult to manufacture or what's the holdup? From that study we should likely all be switching to it based on stability and absorption findings alone.

Edited by Oakman, 27 December 2019 - 01:53 PM.